Asthma is an airways disease characterized by a unique form of chronic inflammation associated with a profile of cytokines produced by the Th2-subset of helper T lymphocytes. Asthma is most often associated with atopy, allergen sensitization, and the IgE response which are also regulated by Th2 cytokines. Using the human model of segmental allergen challenge (SAC), specific recruitment of eosinophils, basophils, and helper/memory T lymphocytes producing Th2 cytokines has been demonstrated, indicating highly selective mechanisms of cellular recruitment involved in the inflammatory response to allergen. This proposal will examine the role of allergen-specific and Th1/Th2 lymphocytes in the inflammatory response and on the subsequent immunologic sensitization of the airway following SAC. The contributions of local immunity and systemic sensitization in directing T-cell recruitment will be examined. The hypothesis to be tested is that lymphocyte recruitment to sites of allergen exposure in the sensitized individual is an allergen-specific process and results in the production of Th2 cytokines which regulate both the inflammatory response and the subsequent immunologic sensitization of the airway. To test our hypothesis, we will define the antigen specificity and function of T-lymphocyte subsets recruited to the sites of allergen challenge in human subjects. We will examine the kinetics of cellular recruitment and its relationship to adhesion molecule/chemokine expression, cytokine production, and production of allergen-specific immunoglobulins in the airways to clarify the relationship between multiple components in the inflammatory and immune response. Finally, in collaboration with Project 1, we will examine the role of tumor necrosis factor-alpha (TNF-a) on T-cell recruitment and function at sites of allergen challenge of the airways. These human studies will yield insights into the mechanisms of allergic inflammation, helper/memory lymphocyte recruitment, and airway sensitization which may guide approaches to treatment.